Carbon Dioxide → 5-chloro-6-fluoro-1H-indole-7-carboxylic acid

HRID 2101260Notes

Reaction equation

HRID 2101260 reaction equation
C([Li])CCC.CCCCCC.[Cl:12][C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][C:21]=1[F:22])[NH:18][CH:17]=[CH:16]2.CC([O-])(C)C.[K+].[C:29](=[O:31])=[O:30]>C1COCC1.O>[Cl:12][C:13]1[CH:14]=[C:15]2[C:19](=[C:20]([C:29]([OH:31])=[O:30])[C:21]=1[F:22])[NH:18][CH:17]=[CH:16]2

Participants

8

Reactant 5

HCID 280Carbon DioxideHCID 8058HexaneHCID 27736475-chloro-6-fluoro-1H-indoleHCID 23665647Potassium tert-butoxideHCID 178418339Butyllithium

Product 1

HCID 251136475-chloro-6-fluoro-1H-indole-7-carboxylic acid

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 8028TetrahydrofuranSolvent3×

Conditions

Temperature
10 °C

Procedure

THF (35 ml) was cooled down to −75° C. under argon and a 1.6M solution of n-butyllithium in hexane (19.05 ml, 30.5 mmol) was added. Then a solution of 5-chloro-6-fluoro-1H-indole (2.35 g, 13.7 mmol) in THF (9 ml) was added over 15 min dropwise keeping the temperature between −70 and −75° C. After additional 5 min stirring at this temperature a solution of potassium tert-butylate (3.7 g) in THF (15 ml) was added over 10 min keeping the temperature between −70 and −75° C. The brown solution was stirred 2 hours at the same temperature and then treated with a large excess of solid carbon dioxide. The temperature was then raised to 10° C. over a period of 75 min, and the reaction was treated with water (30 ml). After separation of the organic phase, the aqueous phase was extracted twice with diethylether (20 ml), treated with concentrated aq. HCl solution until pH 1. The suspension was then filtered, the solid washed with water and dried in high vacuo. The residue was stirred with hexane/diethylether (9/1, 10 ml) for 15 min and filtered, washed with the same solvent mixture (5 ml) and the collected solid dried in high vacuo, leading to 5-chloro-6-fluoro-1H-indole-7-carboxylic acid (2.2 g, 75%) as a light brown solid. MS (ISP): 212.2 (M−H)−.

Workup

  1. customthe temperature between −70 and −75° C
  2. additionwas added over 10 min
  3. customthe temperature between −70 and −75° C
  4. customAfter separation of the organic phase
  5. extractionthe aqueous phase was extracted twice with diethylether (20 ml)
  6. additiontreated with concentrated aq. HCl solution until pH 1
  7. filtrationThe suspension was then filtered
  8. washthe solid washed with water
  9. customdried in high vacuo
  10. stirringThe residue was stirred with hexane/diethylether (9/1, 10 ml) for 15 min
  11. filtrationfiltered
  12. washwashed with the same solvent mixture (5 ml)
  13. customthe collected solid dried in high vacuo

Sources & evidence

ORD record
ord-3243536ba8e543c195efc4df65e8e352
Source dataset
uspto-grants-2009_08
Patent number
US07572823B2

Reaction notes

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